Effects of Polymeric Mucin Expression on Lung Carcinogenesis

聚合粘蛋白表达对肺癌发生的影响

• 批准号: 10369926
• 负责人: Christopher M Evans
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10369926
• 关键词: 3-Dimensional; Address; Adenocarcinoma Cell; Affect; Age; Amino Acids; Anabolism; Animals; Apoptosis; Apoptotic; Binding; Biological Assay; Biology; Cancer Biology; Cancer Etiology; Carcinoma; Cell Line; Cell Nucleus; Cell Proliferation; Cells; Cellular biology; Chemoresistance; Chronic Disease; Data; Development; Dimerization; Disease; Distal; Endoplasmic Reticulum; Enzymes; Epithelial; Epithelial Cells; Family; Functional disorder; Gene Expression; Gene Proteins; Genes; Goals; Goblet Cells; Growth; Health; Host Defense; Human; Imaging Techniques; In Vitro; Individual; Inositol; Intervention; KRAS2 gene; KRASG12D; Knockout Mice; Link; Lung; Lung Adenocarcinoma; MUC5AC gene; MUC5B gene; Malignant Neoplasms; Malignant neoplasm of lung; Mammals; Measures; Mediating; Metabolism; Molecular; Mucinous; Mucins; Mucous Membrane; Mucous body substance; Mus; Mutation; Oncogenic; Pathogenesis; Patients; Pharmacology; Polymers; Populations at Risk; Positioning Attribute; Protein Isoforms; Recurrence; Research; Sampling; Severities; Signal Pathway; Signal Transduction; Signaling Protein; Survival Rate; System; Testing; Tissue imaging; Tobacco smoke; Transgenic Mice; Transgenic Model; Translations; Tumor Burden; Tumor Promotion; Urethane; Vascularization; Veterans; Xenograft procedure; animal imaging; cancer cell; cell growth; coping; demographics; disulfide bond; effective therapy; endoplasmic reticulum stress; experience; glycosylation; human tissue; improved; in vivo; inhibitor; innovation; lung carcinogenesis; molecular imaging; mortality; mortality risk; mouse model; neoplastic cell; novel; overexpression; proteostasis; sensor; service member; sugar; tool; treatment strategy; tumor; tumorigenesis

Lung cancer is the leading cause of cancer-related deaths, and risks are disproportionately high in veterans. Lung adenocarcinoma (LUAD) accounts for half of all lung cancer cases, but effective treatments are lacking in part due to an incomplete understanding of LUAD biology. LUAD tumors originate from airway secretory epithelia, and mucin expression is prevalent and associated with LUAD aggressiveness. However, mechanisms by which mucins affect LUAD pathogenesis are poorly understood. The overarching concept of this proposal is that aberrant epithelial growth in LUAD is potentiated by two polymeric mucins--MUC5AC and MUC5B. Though required for airway defense in health, MUC5AC and MUC5B misexpression in LUAD correlates with invasiveness, recurrence, and mortality, especially in patients with activating mutations in KRAS--the most common oncogenic driver of LUAD. We validated MUC5AC causatively in urethane and activated-Kras expression mouse models of LUAD. In animals lacking Muc5ac (‘MUC in humans, ‘Muc’ in mice), tumor number and size decreased by ~50%. The relative tumor-promoting effects of Muc5b on its own or with Muc5ac are not yet known. We seek to close this significance gap here. We also seek to determine molecular mechanisms for polymeric mucin-mediated tumor promotion. Studies by us and by others have identified numerous signals that stimulate LUAD, including mucinous LUAD subtypes. Upstream signaling pathways converge on mucins and their biosynthetic machinery. Individual MUC5AC and MUC5B molecules are extraordinarily large. They multimerize, and they become even more massive through addition of sugars to their central glycosylation domains. Accordingly, protein homeostasis (proteostasis) is tightly regulated during polymeric mucin biosynthesis. Mucin translation, folding, and dimerization occur in the endoplasmic reticulum (ER) and involve formation of hundreds of disulfide bonds. To handle these demands, mammals express a mucous cell specific isoform of the ER stress sensor inositol-requiring enzyme-1 (IRE-1, also called ER-to- nucleus signaling protein, or ERN). ERN1 is ubiquitously expressed and is crucial for ER stress-triggered apoptosis, but an isoform called ERN2 is restricted to mucous cells where it is required for sustaining mucin synthesis despite high levels of ER stress. This adaptation is accomplished by direct binding of ERN2 to ERN1 and subsequent suppression of ERN1-mediated pro-apoptotic signaling. While beneficial for host defense in health, apoptosis suppression could be detrimental in LUAD. We hypothesize that MUC5AC and MUC5B promote epithelial cell growth in LUAD via ERN2-dependent suppression of ER stress-induced apoptosis. The following three Specific Aims are proposed: 1) Test the hypothesis that MUC5AC/Muc5ac and MUC5B/Muc5b promote LUAD and mucinous LUAD; 2) Test the hypothesis that polymeric mucin expression in tumor cells promotes LUAD via ERN2/Ern2 dependent proteostasis dysfunction; 3) Test the hypothesis that polymeric mucin expression promotes ERN2/Ern2-dependent epithelial growth. Studies will utilize novel mouse models, cell lines, and patient samples to focus on significant causative links between mucins, ER stress, and LUAD. Innovative gene-editing tools will be used along with pharmacologic agents as interventions, and state of the art animal, tissue, and molecular imaging techniques will be applied. Completion of these aims has the potential to significantly impact the lives of veterans and their families. Our team comprises experts in mucin and cancer cell biology who are uniquely positioned to address questions that will improve our understanding of KRAS-induced LUAD. Findings could identify MUC5AC, MUC5B, and ERN2 as targets to directly limit LUAD growth and to improve strategies for this common but poorly treatable form of lung cancer.

肺癌是癌症相关死亡的主要原因，退伍军人的肺癌风险极高。 肺腺癌（LUAD）占所有肺癌病例的一半，但目前缺乏有效的治疗方法 部分原因是对 LUAD 生物学的不完全了解。 上皮细胞和粘蛋白表达普遍存在，并且与 LUAD 侵袭性相关。 粘蛋白影响 LUAD 发病机制的机制尚不清楚。 该提议认为，LUAD 中的异常上皮生长是由两种聚合粘蛋白——MUC5AC 和 MUC5B 虽然是健康气道防御所必需的，但 LUAD 中 MUC5AC 和 MUC5B 表达错误 与侵袭性、复发和死亡率相关，尤其是在具有激活突变的患者中 KRAS——LUAD 最常见的致癌驱动因素，我们验证了 MUC5AC 在聚氨酯和 在缺乏 Muc5ac 的动物中激活 Kras 表达小鼠模型（人类为“MUC”，人类为“Muc”）。 小鼠），肿瘤数量和大小减少了约 50% Muc5b 本身的相对促肿瘤作用。 或与 Muc5ac 尚不清楚，我们也试图在此确定这一显着性差距。 我们和其他人的研究已经揭示了聚合粘蛋白介导的肿瘤促进的分子机制。 确定了许多刺激 LUAD 的信号，包括粘液性 LUAD 亚型。 途径汇聚于粘蛋白及其生物合成机制。 它们非常大，并且通过添加糖而变得更大。 因此，它们的中心糖基化结构域在过程中受到严格调节。 聚合粘蛋白生物合成在内质网中发生。 （ER）并涉及数百个二硫键的形成，为了满足这些需求，哺乳动物表达了一种二硫键。 ER 应激传感器肌醇需求酶 1 (IRE-1，也称为 ER-to- 细胞核信号蛋白 (ERN1) 普遍表达，对于 ER 应激触发至关重要。 细胞凋亡，但一种称为 ERN2 的亚型仅限于粘液细胞，它是维持粘蛋白所必需的 尽管存在高水平的 ER 应激，但仍能合成这种适应是通过 ERN2 直接结合来完成的。 ERN1 和随后抑制 ERN1 介导的促凋亡信号转导同时对宿主有益。 健康防御，细胞凋亡抑制可能会给 LUAD 带来困扰，我们勇敢地说 MUC5AC 和 MUC5B 通过 ERN2 依赖性抑制 ER 应激诱导促进 LUAD 中上皮细胞生长 提出了以下三个具体目标： 1) 检验 MUC5AC/Muc5ac 和细胞凋亡的假设。 MUC5B/Muc5b促进LUAD和粘液性LUAD 2)检验聚合粘蛋白表达的假设； 肿瘤细胞中的 LUAD 通过 ERN2/Ern2 依赖性蛋白质稳态功能障碍促进 LUAD 3) 检验以下假设： 聚合粘蛋白表达促进 ERN2/Ern2 依赖性上皮生长 研究将利用新的方法。 小鼠模型、细胞系和患者样本，重点关注粘蛋白、ER 之间的显着因果关系 创新的基因编辑工具将与药物一起使用。 将应用干预措施以及最先进的动物、组织和分子成像技术。 完成这些目标有可能对退伍军人及其家人的生活产生重大影响。 团队由粘蛋白和癌细胞生物学专家组成，他们在解决问题方面具有独特的优势 这将提高我们对 KRAS 诱导的 LUAD 的理解。研究结果可以识别 MUC5AC、MUC5B 和 ERN2 作为直接限制 LUAD 生长的目标，并改进针对这种常见但难以治疗的策略 肺癌的一种形式。